The present application is a 371 of PCT/JP99/02822 filed on May 28, 1999, which was not published in English under PCT article 21(2), which in turn claims priority to Japanese Patent Application 10-151017 filed Jun. 1, 1998.
The present invention relates to novel cyanoiminoquinoxaline derivatives possessing antagonistic effects on glutamate receptors of central neurons, in particular, NMDA receptors and AMPA receptors.
Amino acids such as L-glutamic acid and L-aspartic acid are indispensable as neurotransmitters for activating neurons in the central nervous system. However, excess accumulation of these excitatory amino acids surrounding neurons is considered to induce hyperexcitation of neurons, causing neurological disorders such as Parkinsonism, senile dementia, Huntington""s disease, and epilepsy; and hyponoia and hypokinesis found after ischemia, anoxia, hypoglycemia, or head and spinal cord trauma (see, McGeer et al. Nature, 263, 517-519 (1976); Simon et al. Science, 226, 850-852 (1984), Wieloch, Science, 230, 681-683 (1985); Faden et al. Science, 244, 798-800 (1989); Turski et al. Nature, 349, 414-418 (1991)).
It has been known that the above-mentioned excitatory amino acids act on the central nervous system neurons via a glutamate receptor on the neurons. Thus, compounds competitively inhibiting the binding of the excitatory amino acids to such a receptor have been considered to be useful as therapeutic or preventive reagents for the above-mentioned diseases and conditions such as antiepileptic, ischemic encephalopathy, and Parkinsonism.
The above-mentioned glutamate receptors can be classified into two groups: an ion channel type and a metabolism type. The ion channel type is further classified into three groups based on its selectivity with respect to binding to the agonist. These three are called N-methyl-D-aspartate (NMDA) receptors, 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoate (AMPA) receptors, and kainate receptors.
The NMDA receptors are selectively activated by agonists such as NMDA and ibotenic acid. Hyperexcitation of the NMDA receptors allows a large amount of calcium ions to flow into neurons, which has been considered one of the causes for the death of neurons. Hithertofore, as antagonists selectively binding to the NMDA receptors, D-2-amino-5-phosphovalerate (D-AP5), 3-[2-carboxypiperazin-4-yl]propyl-1-phosphate (CPP), and the like are known. Further reported is that the NMDA receptors have an allosteric site bound to glycine as well as a site recognizing the above-mentioned agonists, and that the binding of the allosteric site to glycine remarkably enhances the functions of the NMDA receptors. Examples of antagonists to the glycine-binding sites include e.g., 5,7-dichlorokynurenic acid and HA966 (Eur. J. Pharmacol., 151 161-163 (1988)).
The AMPA receptors are selectively activated by agonists such as AMPA, glutamic acid, and quisqualic acid. Examples of the antagonits to the AMPA receptors include compounds having a quinoxaline structure, particularly quinoxaline-2,3-dione derivatives such as 6,7-dinitroquinoxaline-2,3-dione (DNQX), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 2,3-dihydroxy-6-nitro-7-sulfamoylbenzoquinoxaline (NBQX), and 6-imidazolyl-7-nitroquinoxaline-2,3-(1H, 4H)-dione (YM900), 6,7-dichloro-8-nitro-1,4-dihydroxyquinoxaline-2, 3-dione (ACEA1021) (Science,241, 701-703(1988), Eur.J.Pharmacol.,174, 197-204(1989), WO92/07847, JP-A 63-83074, JP-A 63-258466, JP-A 1-153680, JP-A 2-48578, JP-A 2-221263, JP-A 2-221264, Exp. Opin. Ther. Patents (1997) 7 (10), etc.).
Further, compounds to be used as therapeutic agents effective against the above-mentioned diseases and disorders, protecting neurons from death or denaturation caused by the excitatory amino acids, are required to effectively work as antagonists to both of the NMDA receptors and the AMPA receptors (Mosinger et al., Exp. Neurol., 113 10-17 (1991)). Examples of such compounds include quinoxaline-2,3-dione derivatives having a 4-oxo-4H-pyridyl group at the 7-position (JP-A 7-324084, U.S. Pat. No. 5,677,305), quinoxaline-2,3-dione derivatives having an alkylsulfonylimino group at the 2-position (WO97/32858).
In general, most of the known excitatory amino acid antagonists, which have quinoxaline structures therein, precipitate in renal, uriniferou tubule or the like to show side-effects such as nephrotoxicity, as reported on NBQX for example (J. Cerb Blood Flow Metab., Vol. 14, No. 2 (1994)). Thus, the antagonists are difficult to develop and have not practically been utilized as medicines. Further, even if the side-effect could be inhibited to some extent, it was not always easy to maintain the pharmacological effect on the level applicable to clinical use. Accordingly, it has been desired to develop a novel glutamate receptor antagonist which has a quinoxaline structure and can be administered safely to human.
The present inventors have intensively studied to find out that novel quinoxaline derivatives possess potent antagonistic effects on glutamate receptors without side-effects such as nephrotoxicity in the body. The finding is preferably characterized by the conversion of at least one of the oxo (xe2x95x90O) groups at the 2- and 3-positions into a cyanoimino (xe2x95x90NCN) group(s). Further, methods for preparing the present compounds and the intermediates thereof have been found out to accomplish the present invention shown below.
(1) a compound having a quinoxaline structure wherein at least one of the 2- and 3-positions is substituted with a cyanoimino group (hereinafter referred to as a cyanoiminoquinoxaline derivative of the present invention),
(2) a compound described in above (1), which has, in the quinoxaline structure, a partial structure of the formula: 
wherein X and Y each is independently O or NCN, provided that at least one of X and Y is NCN (hereinafter referred to as partial structure (I)),
(3) a compound of the formula: 
xe2x80x83wherein,
X and Y each is independently O or NCN, provided that at least either X and Y is NCN;
R1, R2, R3, and R4 each is independently hydrogen, halogen, nitro, cyano, hydroxy, optionally substituted amino, optionally substituted lower alkyl, optionally substituted lower cycloalkyl, optionally substituted lower alkoxy, optionally substituted lower alkylthio, optionally substituted lower alkylcarbonyl, carbamoyl optionally substituted with lower alkyl, carbamoylamino optionally substituted with lower alkyl, sulfamoyl optionally substituted with lower alkyl, sulfamoylamino optionally substituted with lower alkyl, optionally substituted sulfonyl, optionally substituted aryl, optionally substituted heterocyclic group, or optionally substituted heterocyclylthio;
R5 is hydrogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, or optionally substituted lower cycloalkyl;
R1 and R2, R2 and R3, R3 and R4, and R4 and R5, each together with the atoms adjacent thereto may form a carbocycle which may be substituted or contain a heteroatom(s), the pharmaceutically acceptable salt, or the hydrate thereof (these hereinafter referred to as compound(II)),
(4) a compound (II) described in above (3), wherein X is NCN: Y is O,
(5) a compound (II) described in above (3), wherein X is O; Y is NCN,
(6) a compound (II) described in above (3), wherein both X and Y are NCN,
(7) a compound (II) described in above (3), wherein R5 is hydrogen,
(8) a compound (II) described in above (3), wherein X is NCN; Y is O; R5 is hydrogen,
(9) a compound (II) described in above (3), wherein R1 is hydrogen, halogen, or nitro,
(10) a compound (II) described in above (3), wherein R2 is hydrogen, halogen, nitro, or halogenated lower alkyl,
(11) a compound (II) described in above (3), wherein R3 is hydrogen, halogen, nitro, halogenated lower alkyl, optionally substituted heterocyclic group, or optionally substituted heterocyclylthio,
(12) a compound (II) described in above (3), wherein R4 is hydrogen, halogen, or nitro,
(13) a compound (II) described in above (3), wherein R1 is hydrogen; R2 is hydrogen, halogen, nitro, or halogenated lower alkyl; R3 is hydrogen, halogen, nitro, halogenated lower alkyl, optionally substituted heterocyclic group, or optionally substituted heterocyclylthio; R4 is hydrogen, halogen, or nitro,
(14) a compound (II) described in above (3), wherein X is NCN; Y is O; R1 is hydrogen; R2 is hydrogen, halogen, nitro, or halogenated lower alkyl; R3 is hydrogen, halogen, nitro, halogenated lower alkyl, optionally substituted heterocyclic group, or optionally substituted heterocyclylthio; R4 is hydrogen, halogen, or nitro; R5 is hydrogen,
(15) a compound (II) described in above (3), wherein X is NCN; Y is O; R1 is hydrogen; R2 is halogen, nitro, or trihalogenated methyl; R3 is halogen, nitro, trihalogenated methyl, optionally substituted heterocyclic group, or optionally substituted heterocyclylthio; R4 is hydrogen or nitro; R5 is hydrogen,
(16) a compound (II) described in any one of above (13)-(15), wherein optionally substituted heterocyclic group is 1,4-dihydro-4-oxo-1-pyridyl, 1-imidazolyl or 1-pyrrolyl; heterocyclylthio is 2-imidazolylthio,
(17) a compound (II) described in above (3), wherein X is NCN; Y is O; R1 is hydrogen; R2 is nitro; R3 is 4-oxo-1-pyridyl; R4 is hydrogen; R5 is hydrogen,
(18) a compound described in above (17), which is a monosodium salt of 2-cyanoimino-1,4-dihydro-7-(1,4-dihydro-4-oxo-1-pyridyl)-6-nitro-3-quinoxaline,
(19) a compound described in any one of above (1)-(18), which has an antagonistic effect on glutamate receptors without substantially showing nephrotoxicity upon administration into the body,
(20) a pharmaceutical composition containing a compound described in any one of above (1)-(19),
(21) a pharmaceutical composition having an antagonistic effect on glutamate receptors, which contains a compound described in any one of above (1)-(19),
(22) a pharmaceutical composition for preventing or treating diseases due to hyperexcitation of glutamate receptors, which contains a compound described in any one of above (1)-(19),
(23) a pharmaceutical composition described in above (22), wherein the disease due to hyperexcitation of glutamate receptors is stroke,
(24) a method for preventing or treating diseases due to hyperexcitation of glutamate receptors, which comprises administering a compound described in any one of above (1)-(19),
(25) use of a compound described in any one of above (1)-(19) for preparing a medicament for preventing or treating diseases due to hyperexcitation of glutamate receptors,
(26) a method for preparing a compound (II) of the formula: 
wherein R1, R2, R3 and R4 are the same as defined above, which comprises
1) dealkylating xe2x80x9cR6xe2x80x9d portion of a compound (III-1) of the formula: 
wherein R1, R2, R3 and R4 are the same as defined above; R6 is a hydroxy protecting group, or
2) hydrolyzing xe2x80x9cHalxe2x80x9d portion of a compound (IV-1) of the formula: 
wherein R1, R2, R3 and R4 are the same as defined above; Hal is halogen.
(27) a compound (III-1) or compound (IV-1) described in above (26).
A Cyanoiminoquinoxaline derivative of the present invention means a variety of bi-, tri- or more-cyclic condensed compounds having a quinoxaline structure, wherein at least one of carbon atoms at the 2- and 3-positions is substituted with a cyanoimino group. When only one of the 2- and 3-positions is substituted with cyanoimino, the other is not substituted or substituted with a group such as oxo, halogen, cyano, hydroxy, lower alkoxy (e.g., methoxy, ethoxy, i-propoxy, and tert-butoxy), or carboxyl, alkylsulfonylamino (e.g., methylsulfonylamino).
In a preferred embodiment, a cyanoiminoquinoxaline derivative of the present invention has the above-described partial structure (I) in the quinoxaline structure. In such a case, two N atoms in the partial structure (I) are located at the 1- and 4-positions of quinoxaline. The structure other than the partial structure (I) is a di- or tri-valent group which taken together with the two N atoms can form a condensed ring of ten or more members, and preferred is an optionally substituted divalent benzene ring group.
A cyanoiminoquinoxaline derivative of the present invention is preferably the above-described compound (II). Each substituent of the compound (II) is explained below.
Examples of halogen include F, Cl, Br, and I.
Examples of lower alkyl include straight or branched C1-C6 alkyl, such as methyl, ethyl, i-propyl, tert-butyl, pentyl, and hexyl. Preferred is C1-C4 alkyl.
Examples of lower cycloalkyl include C3-C6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
Examples of lower alkoxy include oxy bonding to the above-described lower alkyl, such as methoxy, ethoxy, i-propoxy, tert-butoxy, pentyloxy, and hexyloxy.
Examples of lower alkylthio include thio bonding to the above-described lower alkyl, such as methylthio, ethylthio, i-propylthio, tert-butylthio, pentylthio, and hexylthio.
Examples of lower alkylcarbonyl include carbonyl bonding to the above-described lower alkyl, such as methylcarbonyl, ethylcarbonyl, i-propylcarbonyl, tert-butylcarbonyl, pentylcarbonyl, and hexylcarbonyl.
Each substituent on amino, lower alkyl, lower cycloalkyl, lower alkoxy, lower alkylthio, or lower alkylcarbonyl is optionally selected from the group consisting of lower alkyl (e.g., methyl, ethyl, propyl, and butyl), lower alkylcarbonyl (e.g., acetyl), lower alkoxycarbonyl (e.g., methoxycarbonyl and ethoxycarbonyl), lower alkoxycarbonylmethyl (e.g., methoxycarbonylmethyl), halogen (e.g., F, Cl, Br, and I), halogenated lower alkyl (esp., trihalogenated methyl (e.g., CF3), optionally substituted amino (e.g., dimethylamino, diethylamino, and benzoylamino), cyano, nitro, carboxy, oxo, carboxymethyl, CHO, PO(OH)2, OPO(OH)2, PO(OCH2CH3)2, SO3H, SO2CH3, SO2CF3optionally substituted phenyl (e.g., phenyl, p-nitrophenyl, p-methylphenyl, and m-chlorophenyl), carbamoyl optionally substituted with lower alkyl (e.g., carbamoyl and methylcarbamoyl), sulfamoyl optionally substituted with lower alkyl (e.g., sulfamoyl, methylsulfamoyl), optionally substituted acylamino (e.g., thienylacetylamino), heterocyclic group (e.g., pyrrolidinyl, thiophenyl, imidazolyl, tetrazolyl, morpholinyl), phenylaminocarbonyl, and benzoylaminoethyl.
Examples of substituents on sulfonyl include lower alkyl (e.g., methyl, ethyl, propyl, and butyl), aryl (e.g., phenyl and naphthyl), and heterocyclic group (e.g., pyrrolidinyl, thiophenyl, imidazolyl, tetrazolyl, and morpholinyl).
Examples of aryl include phenyl and naphthyl.
Examples of heterocyclic group include a 5- to 7-membered aromatic or non-aromatic cyclic group containing 1 to 4, same or different, heteroatom(s) selected from the group consisting of O, S, and N. In the light of pharmacological activity, preferred is a 5- to 6-membered cyclic group containing N atom, such as pyridyl, imidazolyl, triazolyl, pyrrolyl, and piperidyl, and more preferred is 1,4-dihydro-1-pyridyl, 1-imidazolyl, and 1-pyrrolyl.
Examples of heterocyclylthio include thio bonding to the above-described heterocyclic group, such as pyridylthio, imidazolylthio, triazolylthio, pyrrolylthio, and piperidylthio, and preferred is 2-imidazolylthio.
Examples of each substituent on the above-described aryl, heterocyclic group, or heterocyclylthio include 1 to 4 group(s) optionally selected from the group consisting of oxo, thioxo, halogen, nitro, cyano, amino, acylamino (e.g., acetylamino, benzoylamino, and pyridylcarbonylamino), acylaminomethyl (e.g., acetylaminomethyl), di(lower)alkylamino (e.g., dimethylamino), carboxy, lower alkyl (e.g., methyl and ethyl), halogenated lower alkyl (e.g., trifluoromethyl), carboxy lower alkyl (e.g., carboxymethyl), lower alkoxy (e.g., methoxy and ethoxy), halogenated lower alkoxy (e.g., trifluoromethoxy), lower alkoxycarbonyl (e.g., methoxycarbonyl), lower alkoxymethyl (e.g., methoxymethyl), lower alkoxycarbonylmethyl (e.g., methoxycarbonylmethyl), carbamoyl optionally substituted with lower alkyl (e.g., methylcarbamoyl), carbamoylamino optionally substituted with lower alkyl (e.g., methylcarbamoylamino), sulfamoylamino optionally substituted with lower alkyl (e.g., methylsulfamoylamino), SO3H, SO2NH2, NHCSNH2, NHCSH, NHSO2NH, NHSO2CF3, optionally substituted aryl (e.g., halogenated phenyl), pyridylcarbamoylmethyl, piperazinylcarbonyl, and heterocyclic group (e.g., pyridyl), and preferred is oxo.
Examples of xe2x80x9ccarbocycle containing a hetero atom(s)xe2x80x9d which is formed by any combination of R1 and R2, R2 and R3, R3 and R4, and R4 and R5, together with the adjacent atoms, include a 5- to 7-membered ring which may contain 1 to 4, same or different, hetero atom(s) selected from the group consisting of O, S, and N, such as benzene, thiophen, pyrrole, pyrrolidine, imidazole, oxazole, thiazole, imidazoline, imidazolidine, oxazolidine, pyridine, pyran, thiopyran, piperidine, piperadine, morphorino, and triazole. These groups may have a substitute(s) similar to those mentioned as to the above-described heterocyclic group.
Preferred examples of each group are shown below.
X and Y is preferably NCN and 0, respectively.
R1 is preferably hydrogen, halogen, nitro, methylsulfonylamino, (N-carboxymethyl)methylsulfonylamino, more preferably hydrogen, halogen, or nitro, and particularly hydrogen.
R2 is preferably hydrogen, halogen, nitro, halogenated lower alkyl (e.g., trifluoromethyl), cyano, carboxyl, lower alkyl (e.g., methyl), lower alkoxy (e.g., methoxy), halogenated lower alkoxy (e.g., trifluoromethoxy), lower alkylthio (e.g., methylthio), halogenated lower alkylthio (e.g., trifluoromethylthio), di-lower alkylamino (e.g., dimethylamino), optionally substituted aryl (e.g., 4-chlorophenyl), optionally substituted heterocyclic group (e.g., 1,4-dihydro-4-oxo-1-pyridyl, 1-imidazolyl, 1-pyrrolyl, and 3-carboxy-1-pyrrolyl), optionally substituted heterocyclylthio, lower alkylsulfonyl (e.g., methylsulfonyl), or lower alkylaminosulfonyl (e.g., methylaminosulfonyl), more preferably halogen (e.g., Cl), nitro, or trihalogenated methyl (e.g., trifluoromethyl), and particularly nitro.
R3 is preferably hydrogen, halogen, nitro, halogenated lower alkyl(e.g., trifluoromethyl), cyano, lower alkyl (e.g., methyl), optionally substituted lower alkoxy (e.g., diethylaminoethoxy), halogenated lower alkoxy (e.g., trifluoromethoxy), lower alkylthio (e.g., methylthio), halogenated lower alkylthio (e.g., trifluoromethylthio), di-lower alkylamino (e.g., dimethylamino), (N-carboxymethyl)methylsulfonylamino, optionally substituted aryl (e.g., 4-chlorophenyl), optionally substituted heterocyclic group, optionally substituted heterocyclylthio, lower alkylsulfonyl (e.g., methylsulfonyl), or lower alkylaminosulfonyl (e.g., methylaminosulfonyl), and more preferably halogen (e.g., Cl), nitro, trihalogenatedmethyl (e.g., trifluoromethyl), optionally substituted heterocyclic group (e.g., 1,4-dihydro-4-oxo-1-pyridyl, 1-imidazolyl, 1-pyrrolyl, 3-carboxyl-pyrrolyl), or optionally substituted heterocyclylthio (e.g., 1-imidazolylthio), particularly 1,4-dihydro-4-oxo-1-pyridyl.
R4 is preferably hydrogen, halogen, nitro, 5-methyl-1-tetrazolyl, 3-thienylacetylamino, dimethylaminomethyl, or pyrrolidinylmethyl, more preferably hydrogen, halogen, or nitro, and particularly hydrogen.
R5 is preferably hydrogen, lower alkyl (e.g., methyl, ethyl, and propyl), carboxymethyl, xe2x80x94CH2PO(OEt)2, or xe2x80x94CH2PO(OH)2, more preferably hydrogen.
A cyanoiminoquinoxaline derivative of the present invention can be prepared through reactions well known to a parson skilled in the art. One of the representative methods is a process converting xe2x80x9coxoxe2x80x9d to xe2x80x9ccyanoiminoxe2x80x9d at the 2- and/or 3-position of quinoxaline-2,3-dione derivatives, which are known materials or easily synthesized by a person skilled in the art. Preferably, a cyanoimino group(s) can be introduced to the 2- and/or 3-position of a 1,4-dihydro-quinoxaline-2,3-dione derivative, by halogenating the oxo parts at the 2- and 3-positions, followed by the reaction with 2 equivalents of cyanoiminating reagent. Otherwise, the introduction of a cyanoimino group(s) at the 2- and/or 3-position can be carried out by converting at least one of the halogens in advance, followed by the reaction with an equivalent of a cyanoiminating reagent. Further, the oxo atoms at the 2- and 3-positions can be converted to alkoxy groups, followed by changing any of R1-R5 groups to the other substituent(s), then an equivalent of a cyanoiminating reagent is used to introduce a cyanoimino group(s) at the 2- or 3-position. Further, the obtained cyanoiminoquinoxaline derivative can be chemically modified to give the other compound of the present invention. In the above-described processes, R1-R5 each can be converted to the other substituent, if necessary. General methods of compound (II) are shown below. The methods and all the novel intermediates thereof are encompassed in the present invention. Compound (III-1), compound (IV-1), or the like is useful as an intermediate for compound (II). 
(1) Compound (VII)xe2x86x92Compound (VI)
Halogenation is carried out to oxo at the 2- and 3-positions of compound (VII), 1,4-dihydro-quinoxaline-2,3-dione derivative, according to the method well known to a person skilled in the art. Examples of the halogenating reagent include phosphorus oxychloride, thionyl chloride, phosphorus pentachloride, and phosphorus tribromide. A solvent may be used if necessary, such as benzene, toluene, N,N-dimethylaniline, methylene chloride, and chloroform. Further if necessary, a reaction accelerating reagent may used, such as DMF (N,N-dimethylformamide). The reaction temperature is usually about 0 to 200xc2x0 C., preferably about 50 to 150xc2x0 C.
Part of Compound (VII) is known in the above-described prior arts such as JP-A H07-324084, JP-A H08-59660, and WO97/32858, or the compound can be prepared according to the methods described therein. Some of compound (VI) are also described in WO97/32858. In the above-described reaction scheme, the position-numbering of the quinoxaline structure of compound (VII) is ruled as shown above for convenience, and the rule applies to the derivatives thereof.
(2) Compound (VI)xe2x86x92Compound (IV-1, IV-2)
Either halogen at the 2- and 3-positions of compound (VI) is converted into cyanoimino by the method well known to a person skilled in the art. Examples of the reagent include sodium hydridelcyanamide, monosodium cyanamide, and disodium cyanamide. Examples of the solvent include, DMF, DMSO (dimethylsulfoxide), N-methylpyrrolidone, and N,N-dimethylacetamide. The reaction temperature is usually about xe2x88x9220 to 50xc2x0 C., preferably 0 to 20xc2x0 C.
(3) Compound (IV-1, IV-2)xe2x86x92Compound (II-1, II-2)
Each halogen part of compound (IV-1) and (IV-2) is hydrolized converting it into oxo by the method well known to a person skilled in the art. Examples of the hydrolizing reagent include a base such as NaOH and KOH. Examples of the solvent include e.g., water and hydrated alcohol. The reaction temperature is usually about 0 to 80xc2x0 C., preferably about 20 to 50xc2x0 C.
(4) Compound (VI)xe2x86x92Compound (V-1,V-2)
Each halogen at the 2- and/or 3-position of compound (VI) is converted into a protected hydroxy by the method well known to a person skilled in the art. In the above reaction scheme, Z means halogen or OR6 and R6 is a hydroxy protecting group. Examples of the reagent include potassium t-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium isopropoxide, and sodium benzyloxide. Examples of the solvent include t-BuOH, MeOH, EtOH, PrOH, i-PrOH, toluene, THF (tetrahydrofran), and DMF. The reaction temperature is usually about xe2x88x9220 to 50xc2x0 C., preferably xe2x88x9210 to 20xc2x0 C.
The hydroxy protecting group shown of R6 is not particularly limited, and preferred is lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, and tert-butyl), or benzyl.
(5) Compound (V-1,V-2)xe2x86x92Compound (III-1, III-2)
Z part (halogen or OR6) of compound (V-1) or (V-2) is converted into cyanoimino by the method well known to a person skilled in the art. Examples of the reagent include sodium hydride/cyanamide, monosodium cyanamide, disodium and cyanamide. Examples of the solvent include DMF, DMSO, N-methylpyrrolidone, N,N-dimethylacetamide, and toluene. The reaction temperature is usually about xe2x88x9220 to 50xc2x0 C., preferably xe2x88x9210 to 20xc2x0 C.
(6) Compound (III-1, III-2)xe2x86x92Compound (II-1, II-2)
OR6 of compound (III-1) or (III-2) is dealkylated to convert it into oxo by the methods well known to a person skilled in the art. In case of the de-alkylation under acidic conditions, examples of the reagent include acids such as hydrogen chloride, and trifluoroacetic acid; examples of the solvent include ethyl acetate, toluene, methylene chloride, and chloroform, and the reaction temperature is usually about xe2x88x9220 to 50xc2x0 C., preferably xe2x88x9210 to 20xc2x0 C. In case of the dealkylation under basic conditions, examples of the reagent include NaOH and KOH; examples of the solvent include water, DMSO, DMF, and N-methylpyrrolidone, and the reaction temperature is about 0 to 100xc2x0 C., preferably about 20 to 80xc2x0 C.
(7) Compound (II-1, II-2)xe2x86x92Compound (II-1a, II-2a)
R5 is introduced to the 1-N-position of compound (II-1) or (II-2) by the method well known to a person skilled in the art. Examples of the reagent include various electrophilic reagents having the R5 group, such as alkyl halide (e.g., Mel and EtBr), alkyl phosphonate (e.g., diethyl chloromethylphosphonate), and ethyl chloroacetate.
Examples of the solvent include THF and DMF. The reaction temperature is usually about 0 to 50xc2x0 C., preferably about 0 to 20xc2x0 C.
(8) Compound (VI)xe2x86x92Compound (II-3)
Both Halogens at the 2- and 3-positions of compound (VI) is converted into cyanoimino by the method well known to a person skilled in the art. Examples of the reagent include sodium hydride/cyanamide, monosodium cyanamide, and disodium cyanamide. Examples of the solvent include DMF, DMSO, N-methylpyrrolidone, and N,N-dimethylacetamide. The reaction temperature is usually about xe2x88x9220 to 50xc2x0 C., preferably xe2x88x9210 to 20xc2x0 C.
In the above-described reactions, appropriate protection to a functional group can be carried out in advance, and if necessary, the deprotection after the reaction(s), according to the method well known to a person skilled in the art.
Examples of salts of a cyanoiminoquinoxaline derivative of the present invention include various types which are formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, or halogen ion, and the inner salts. Examples of the inorganic bases include alkali metals (e.g., Na and K), alkaline-earth metals (e.g., Ca and Mg). Examples of the organic bases include trimethylamine, triethylamine, coline, procaine, and ethanolamine. Preferred is Na salts. Examples of the inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of the organic acids include xcfx81-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetate, and maleic acid. Examples of the basic amino acids include lysine, arginine, ornithine, and histidine. The derivatives of the present invention may be hydrates (e.g., dihydrate) or solvates.
A Cyanoiminoquinoxaline derivative of the present invention may be various kinds of steroisomers depending upon conditions, and all of the theoretically possibe steroisomers and mixtures thereof are included within the scope of the present invention. For example, compound (II) wherein R5 is H may be in the equilibrium state shown below. 
A Cyanoiminoquinoxaline derivative of the present invention can be a preventive or therapeutic agent for central nerve diseases caused by the binding of excitatory amino acids to the NMDA receptors, particularly to glycine-binding sites and AMPA receptors. Examples of the central nerve diseases include Parkinsonism, senile dementia, Huntington""s disease, and epilepsy, cerebral infarction, stroke, ischemic cerebral disorder or the like.
A composition of the present invention is preferably an injectable solution or suspension, though it may be other formulations such as granules, tablets, and capsules. The composition may contain, if necessary, various additives such as physiologic saline, D-glucose, pH adjusting agents, disintegrating agents, solubilizing agents, excipients, and stablizers.
A compound of the present invention can be administered orally or parenterally, esp. intravenously, to humans. The dose may be varied depending upon the age, weight, and condition of patients, expected effects, or the administration route or time. In general, the dose for oral administration is about 1-1000 mg, preferably 10-500 mg; and for parenteral use it is about 1-500 mg, per an adult and a day. The compound can be administered in one to several divisions a day or continuously.